scholarly journals The architecture of the human RNA-binding protein regulatory network

2016 ◽  
Author(s):  
Alessandro Quattrone ◽  
Erik Dassi
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Regulatory Network ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Hierarchical Structures ◽  
Systematic Investigation ◽  
Regulatory Structure ◽  
Post Transcriptional Regulation

AbstractRNA-binding proteins (RBPs) are key players of post-transcriptional regulation of gene expression. These proteins influence both cellular physiology and pathology by regulating processes ranging from splicing and polyadenylation to mRNA localization, stability, and translation. To fine-tune the outcome of their regulatory action, RBPs rely on an intricate web of competitive and cooperative interactions. Several studies have described individual interactions of RBPs with RBP mRNAs, suggestive of a RBP-RBP regulatory structure. Here we present the first systematic investigation of this structure, based on a network including almost fifty thousand experimentally determined interactions between RBPs and bound RBP mRNAs.Our analysis identified two features defining the structure of the RBP-RBP regulatory network. What we call “RBP clusters” are groups of densely interconnected RBPs which co-regulate their targets, suggesting a tight control of cooperative and competitive behaviors. “RBP chains”, instead, are hierarchical structures driven by evolutionarily ancient RBPs, which connect the RBP clusters and could in this way provide the flexibility to coordinate the tuning of a broad set of biological processes.The combination of these two features suggests that RBP chains may use the modulation of their RBP targets to coordinately control the different cell programs controlled by the RBP clusters. Under this island-hopping model, the regulatory signal flowing through the chains hops from one RBP cluster to another, implementing elaborate regulatory plans to impact cellular phenotypes. This work thus establishes RBP-RBP interactions as a backbone driving post-transcriptional regulation of gene expression to allow the fine-grained control of RBPs and their targets.

scholarly journals The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1539 ◽  
Author(s):  
Yogesh Saini ◽  
Jian Chen ◽  
Sonika Patial
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Finger Protein ◽  
Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

scholarly journals Distinct Hypoxia-induced Translational Profiles of Embryonic and Adult-derived Macrophages

2021 ◽  
Author(s):  
Nicholas S. Wilcox ◽  
Timur O. Yarovinsky ◽  
Prakruti Pandya ◽  
Vinod S. Ramgolam ◽  
Albertomaria Moro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Binding ◽  
Environmental Changes ◽  
Rna Binding Proteins ◽  
Fetal Liver ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Translation Rate ◽  
Post Transcriptional Regulation

SummaryTissue homeostasis and repair are orchestrated by resident and newly recruited macrophages that alter their gene expression program in response to changes in tissue microenvironment. Embryonic macrophages, such as fetal liver derived macrophages (FLDM) seed the organs, including heart and lung during embryonic development and persist throughout the adult lifetime, while bone marrow-derived macrophages (BMDM) are recruited following an acute perturbation. Transcriptome analyses of FLDM and BMDM identified differences between them at the level of RNA expression, which correlates imperfectly with protein levels. Post-transcriptional regulation by microRNAs (miRNAs) and RNA-binding proteins determines mRNA stability and translation rate and may override transcriptional cues in response to environmental changes, such as hypoxia. To identify distinct features of FLDM and BMDM response to hypoxia at the level of translation, we employed translating ribosome affinity purification (TRAP) to isolate polysomal RNA. RNA-seq profiling of translated RNA identified distinct hypoxia-induced translational signature of BMDM (Ly6e, vimentin and glycolysis-associated enzymes Pgk1, Tpi1, Aldoa, Ldha) and FLDM (chemokines Ccl7 and Ccl2). By translational profiling of BMDM and FLDM with deletion of the RNA-binding protein HuR, we identified transcripts that were dependent on HuR. These findings highlight the importance of HuR and identify its distinct targets for post-transcriptional regulation of gene expression in embryonic vs. adult-derived macrophages.

scholarly journals PSDX: A Comprehensive Multi-Omics Association Database of Populus trichocarpa With a Focus on the Secondary Growth in Response to Stresses

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiyuan Wang ◽  
Sheng Liu ◽  
Xiufang Dai ◽  
Yongkang Yang ◽  
Yunjun Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Transcription Initiation ◽  
High Throughput Sequencing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Populus Trichocarpa ◽  
Secondary Growth ◽  
A Genome ◽  
Post Transcriptional Regulation

Populus trichocarpa (P. trichocarpa) is a model tree for the investigation of wood formation. In recent years, researchers have generated a large number of high-throughput sequencing data in P. trichocarpa. However, no comprehensive database that provides multi-omics associations for the investigation of secondary growth in response to diverse stresses has been reported. Therefore, we developed a public repository that presents comprehensive measurements of gene expression and post-transcriptional regulation by integrating 144 RNA-Seq, 33 ChIP-seq, and six single-molecule real-time (SMRT) isoform sequencing (Iso-seq) libraries prepared from tissues subjected to different stresses. All the samples from different studies were analyzed to obtain gene expression, co-expression network, and differentially expressed genes (DEG) using unified parameters, which allowed comparison of results from different studies and treatments. In addition to gene expression, we also identified and deposited pre-processed data about alternative splicing (AS), alternative polyadenylation (APA) and alternative transcription initiation (ATI). The post-transcriptional regulation, differential expression, and co-expression network datasets were integrated into a new P. trichocarpa Stem Differentiating Xylem (PSDX) database, which further highlights gene families of RNA-binding proteins and stress-related genes. The PSDX also provides tools for data query, visualization, a genome browser, and the BLAST option for sequence-based query. Much of the data is also available for bulk download. The availability of PSDX contributes to the research related to the secondary growth in response to stresses in P. trichocarpa, which will provide new insights that can be useful for the improvement of stress tolerance in woody plants.

scholarly journals RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

2020 ◽  
Vol 21 (18) ◽  
pp. 6835
Author(s):  
Jonas Weiße ◽  
Julia Rosemann ◽  
Vanessa Krauspe ◽  
Matthias Kappler ◽  
Alexander W. Eckert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Invasion And Metastasis ◽  
Protein Coding ◽  
Oral Cancers ◽  
Cellular Processes ◽  
Post Transcriptional Regulation

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.

Post-transcriptional regulation of gene expression by Unr

2015 ◽  
Vol 43 (3) ◽  
pp. 323-327 ◽  
Author(s):  
Swagat Ray ◽  
Pól Ó Catnaigh ◽  
Emma C. Anderson
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Protein Interactions ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Negative Regulator ◽  
Cellular Translation ◽  
Cellular Mrnas ◽  
Internal Initiation ◽  
Post Transcriptional Regulation

Unr (upstream of N-ras) is a eukaryotic RNA-binding protein that has a number of roles in the post-transcriptional regulation of gene expression. Originally identified as an activator of internal initiation of picornavirus translation, it has since been shown to act as an activator and inhibitor of cellular translation and as a positive and negative regulator of mRNA stability, regulating cellular processes such as mitosis and apoptosis. The different post-transcriptional functions of Unr depend on the identity of its mRNA and protein partners and can vary with cell type and changing cellular conditions. Recent high-throughput analyses of RNA–protein interactions indicate that Unr binds to a large subset of cellular mRNAs, suggesting that Unr may play a wider role in translational responses to cellular signals than previously thought.

MicroRNAs Act as Decoy Molecules To Restore Granulocytic Maturation of Differentiation-Arrested BCR/ABL+ Myeloid Precursors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 31-31 ◽  
Author(s):  
Anna M. Eiring ◽  
Paolo Neviani ◽  
George A. Calin ◽  
Denis C. Roy ◽  
Carlo M. Croce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Myelogenous Leukemia ◽  
Imatinib Treatment ◽  
E2 Protein ◽  
Post Transcriptional Regulation

Abstract Altered microRNA (miR) expression contributes to aberrant post-transcriptional regulation of gene expression in different type of cancers; however, their role in the pathogenesis and progression of chronic myelogenous leukemia (CML) from chronic phase (CML-CP) to blast crisis (CML-BC) is still largely unknown. Microarray analysis of miR expression reveals that a discrete number of miRs are significantly upregulated (∼ 6.7% of the total 505 miRs present on the chip; 34 miRs) or downregulated (∼2.8% of the miRs present on the chip; 14 miRs) in an imatinib-sensitive manner in CML-BCCD34+ compared to CML-CPCD34+ progenitors and in BCR/ABL-expressing hematopoietic cell lines compared to untransformed parental cells. Among them, we focused our attention on miR-223, miR-15a/16-1 and miR-328, a microRNA with no currently known function, because of their importance in myelopoiesis, potential role as tumor suppressors and sequence homology with the 5’UTR of CEBPA mRNA, respectively. In 32D-BCR/ABL and K562 cells, Northern blot and TaqMan RT-PCR analyses revealed that expression of miR-223, miR-328, miR-15a and miR-16-1 was markedly suppressed (50–75% inhibition) by p210-BCR/ABL kinase activity and that imatinib treatment (1mM; 24h) restored the expression of these miRs to levels similar to those detected in non-transformed 32Dcl3 cells. Interestingly, sequence analysis of both miR-223 and miR-328 revealed homology with the hnRNP E2-binding site contained in the CEBPA uORF/spacer mRNA, a known target of the negative regulator of myeloid differentiation hnRNP E2. Accordingly, REMSA and UV-crosslinking experiments showed that synthetic miR-223 and to a greater extent miR-328 bind efficiently to recombinant hnRNP E2 protein and compete for its binding to an oligoribonucleotide containing the CEBPA uORF/spacer region, which is required for hnRNP E2-mediated translational inhibition of CEBPA in CML-BCCD34+ progenitors. Furthermore, both miR-223 and miR-328 bind endogenous hnRNP E2 from lysates of BCR/ABL-expressing but not parental cells, and from lysates of parental 32Dcl3 myeloid precursors ectopically expressing a Flag-tagged hnRNP E2 protein, suggesting that miR-223 and miR-328 may act as decoy molecules that interfere with the translation-inhibitory activity of hnRNP E2. Indeed, ectopic expression of miR-223 restored G-CSF-driven granulocytic maturation of differentiation-arrested 32D-BCR/ABL cells and restored C/EBPα expression, whereas it did not have any effect on cytokine-independent growth and clonogenic potential. Consistent with its ability to bind hnRNP E2, miR-328 also rescued C/EBPα expression and differentiation of cytokine-independent BCR/ABL-expressing myeloid precursor 32Dcl3 cells. By contrast, BCR/ABL-dependent colony formation was markedly reduced by overexpression of miR-15a and miR-16-1 (65–75% inhibition, P<0.001) and slightly decreased (40–50% inhibition, P<0.01) by ectopic miR-328 expression. Altogether, these data not only reinforce the importance of BCR/ABL-dependent post-transcriptional regulation of gene expression during CML disease progression but also suggest a new function for microRNAs as functional regulators of RNA binding proteins involved in the control of malignant cell growth, survival and differentiation.

scholarly journals Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of proteins and miRNAs

2016 ◽  
Author(s):  
Mireya Plass ◽  
Simon H. Rasmussen ◽  
Anders Krogh
Keyword(s):  
Transcriptional Regulation ◽  
Mirna Target ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Regulatory Control ◽  
Hek293 Cells ◽  
Transcriptional Level ◽  
Target Sites ◽  
Post Transcriptional Regulation

AbstractBackgroundMicroRNAs (miRNAs) are endogenous short non-coding RNAs involved in the regulation of gene expression at the post-transcriptional level typically by promoting destabilization or translational repression of target RNAs. Sometimes this regulation is absent or different, which likely is the result of interactions with other post-transcriptional factors, particularly RNA-binding proteins (RBPs). Despite the importance of the interactions between RBPs and miRNAs, little is known about how they affect post-transcriptional regulation in a global scale.ResultsIn this study, we have analyzed CLIP datasets of 49 RBPs in HEK293 cells with the aim of understanding the interplay between RBPs and miRNAs in post-transcriptional regulation. Our results show that RBPs bind preferentially in conserved regulatory hotspots that frequently contain miRNA target sites. This organization facilitates the competition and cooperation among RBPs and the regulation of miRNA target site accessibility. In some cases RBP enrichment on target sites correlates with miRNA expression, suggesting coordination between the regulatory factors. However, in most cases, competition among factors is the most plausible interpretation of our data. Upon AGO2 knockdown, transcripts that contain such hotspots that overlap target sites of expressed miRNAs in 3’UTRs are significantly less up-regulated than transcripts without them, suggesting that RBP binding limits miRNA accessibility.ConclusionsWe show that RBP binding is concentrated in regulatory hotspots in 3’UTRs. The presence of these hotspots facilitates the interaction among post-transcriptional regulators, that interact or compete with each other under different conditions. These hotspots are enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are important regulatory regions that define an extra layer of auto-regulatory control of post-transcriptional regulation.

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